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Lapatinib Combined With Letrozole Versus Letrozole and Placebo As First-Line Therapy for Postmenopausal Hormone Receptor-Positive Metastatic Breast Cancer.

Author(s): Johnston S, Pippen J Jr, Pivot X, Lichinitser M, Sadeghi S, Dieras V, Gomez HL, Romieu G, Manikhas A, Kennedy MJ, Press MF, Maltzman J, Florance A, O'Rourke L, Oliva C, Stein S, Pegram M

Affiliation(s): Royal Marsden Hospital, London; GlaxoSmithKline, Middlesex, United Kingdom; Sammons Cancer Center, Dallas, TX; David Geffen School of Medicine; University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA; GlaxoSmithKline, Collegeville, PA; GlaxoSmithKline, Durham, NC; University of Miami Sylvester Comprehensive Cancer Center, Miami, FL; University Hospital J. Minjoz, L'Institut National de la Sante et de la Recherche Medicale Unit 645, Besancon; Institut Curie, Paris; Department of Medical Oncology, CRLC Val d'Aurelle, Montpellier, France; Cancer Research Center, Moscow; City Clinical Oncology Dispensary, St Petersburg, Russia; Instituto De Enfermedades Neoplasicas, Lima, Peru; and The All-Ireland Cooperative Oncology Research Group, Dublin, Ireland.

Publication date & source: 2009-09-28, J Clin Oncol., [Epub ahead of print]

PURPOSE: Cross-talk between human epidermal growth factor receptors and hormone receptor pathways may cause endocrine resistance in breast cancer. This trial evaluated the effect of adding lapatinib, a dual tyrosine kinase inhibitor blocking epidermal growth factor receptor and human epidermal growth factor receptor 2 (HER2), to the aromatase inhibitor letrozole as first-line treatment of hormone receptor (HR) -positive metastatic breast cancer (MBC). PATIENTS AND METHODS: Postmenopausal women with HR-positive MBC were randomly assigned to daily letrozole (2.5 mg orally) plus lapatinib (1,500 mg orally) or letrozole and placebo. The primary end point was progression-free survival (PFS) in the HER2-positive population. RESULTS: In HR-positive, HER2-positive patients (n = 219), addition of lapatinib to letrozole significantly reduced the risk of disease progression versus letrozole-placebo (hazard ratio [HR] = 0.71; 95% CI, 0.53 to 0.96; P = .019); median PFS was 8.2 v 3.0 months, respectively. Clinical benefit (responsive or stable disease >/= 6 months) was significantly greater for lapatinib-letrozole versus letrozole-placebo (48% v 29%, respectively; odds ratio [OR] = 0.4; 95% CI, 0.2 to 0.8; P = .003). Patients with centrally confirmed HR-positive, HER2-negative tumors (n = 952) had no improvement in PFS. A preplanned Cox regression analysis identified prior antiestrogen therapy as a significant factor in the HER2-negative population; a nonsignificant trend toward prolonged PFS for lapatinib-letrozole was seen in patients who experienced relapse less than 6 months since prior tamoxifen discontinuation (HR = 0.78; 95% CI, 0.57 to 1.07; P = .117). Grade 3 or 4 adverse events were more common in the lapatinib-letrozole arm versus letrozole-placebo arm (diarrhea, 10% v 1%; rash, 1% v 0%, respectively), but they were manageable. CONCLUSION: This trial demonstrated that a combined targeted strategy with letrozole and lapatinib significantly enhances PFS and clinical benefit rates in patients with MBC that coexpresses HR and HER2.

Page last updated: 2009-10-20

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